CN111635448B

CN111635448B - Method for treating cyproterone acetate mother liquor

Info

Publication number: CN111635448B
Application number: CN202010449557.9A
Authority: CN
Inventors: 蔡啸; 狄飞飞; 徐仙凤; 应娟; 刘林
Original assignee: Hubei Gedian Humanwell Pharmaceutical Co ltd
Current assignee: Hubei Gedian Humanwell Pharmaceutical Co ltd
Priority date: 2020-05-25
Filing date: 2020-05-25
Publication date: 2023-04-14
Anticipated expiration: 2040-05-25
Also published as: CN111635448A

Abstract

The invention relates to a method for treating cyproterone acetate mother liquor, which comprises the following steps: 1) Providing oily mother liquor after CPA industrial production of concentrated dry solvent generated in the CPA synthesis process, adding mixed solvent into the mother liquor to dissolve, filtering out jelly, carrying out column chromatography elution by using the mixed solvent to obtain washing liquid containing CPA and CPA chloride with small polarity, and collecting for later use; 2) Eluting and collecting CPA hydrolysis impurities and CPA chloride hydrolysis impurities in the chromatographic column, and performing 17-position esterification reaction to correspondingly convert the CPA hydrolysis impurities and the CPA chloride hydrolysis impurities into CPA and CPA chloride; 3) And (3) mixing the washing liquid of the CPA and the CPA chloride obtained in the step (1) with the CPA and the CPA chloride obtained by conversion in the step (2), and dehydrochlorinating under alkaline conditions to carry out cyclization to prepare the CPA. The method can convert impurities in the mother liquor into CPA and effectively separate and purify the CPA, and the recovery rate of the CPA in the mother liquor is up to 70%.

Description

Method for treating cyproterone acetate mother liquor

Technical Field

The invention belongs to the technical field of organic chemistry, and relates to a method for treating a cyproterone acetate mother liquor.

Background

Cyproterone acetate (CPA) is a 17 alpha hydroxy pregnone derivative, an androgen antagonist, has strong anti-androgen effect and also has progestational activity. The traditional Chinese medicine composition is clinically used for treating male sexual desire abnormality, puberty precocity, female hirsutism, acne, prostatic hyperplasia, prostate cancer and the like. It is widely used as a compound contraceptive medicament prepared by other progestogens.

The final step of the current industrial synthesis is obtained by dehydrochlorination of CPA chloride under the alkaline conditions of calcium hydroxide, sodium hydroxide and the like, and because the 17-acetyl ester group of CPA chloride is sensitive to alkali, a relatively large amount of ester hydrolysis impurities, namely CPA hydrolysis impurities, are often generated in the reaction, and CPA chloride is also hydrolyzed to generate partial CPA chloride hydrolysis impurities:

because the CPA hydrolysis impurities, the CPA chloride hydrolysis impurities and the CPA chloride which is not completely reacted exist, the effect of final refining crystallization is greatly influenced, more products cannot be separated out, and finally the products and impurities enter mother liquor, so that the yield of a product is low. The mother liquor is oily after the solvent is removed by evaporation, cannot be crystallized by conventional solvent refining, is difficult to treat and can only be discarded, the materials cannot be fully utilized, and meanwhile, the environment is polluted.

Disclosure of Invention

The invention aims to solve the technical problem of providing a cyproterone acetate mother liquor treatment method with strong operability and high material utilization rate aiming at the defects in the prior art, and the CPA recovery rate can reach 70% and the purity is more than or equal to 99.5% by adopting the method.

In order to solve the technical problems, the technical scheme provided by the invention is as follows:

the method for treating the cyproterone acetate mother liquor comprises the following steps:

1) Providing oily mother liquor generated in the CPA synthesis process after CPA industrial production of concentrated dry solvent, wherein the mother liquor contains CPA, CPA hydrolysis impurities, CPA chloride hydrolysis impurities and CPA chloride, adding a mixed solvent into the mother liquor, filtering to remove jelly, eluting by using the mixed solvent column chromatography, eluting CPA and CPA chloride with low polarity based on the polarity of the CPA and CPA chloride and the polarity difference of the CPA hydrolysis impurities and the CPA chloride hydrolysis impurities, obtaining a washing liquid containing the CPA and CPA chloride with low polarity, and collecting for later use;

2) Eluting and collecting CPA hydrolysis impurities and CPA chloride hydrolysis impurities in the chromatographic column, and performing 17-position esterification reaction to correspondingly convert the CPA hydrolysis impurities and the CPA chloride hydrolysis impurities into CPA and CPA chloride;

3) And (2) mixing the washing liquid of the CPA and the CPA chloride obtained in the step 1) with a concentrated dry solvent and the CPA chloride obtained by conversion in the step 2), and dehydrochlorinating under an alkaline condition to carry out cyclization to prepare the CPA.

According to the scheme, the mixed solvent in the step 1) is a mixture of a good solvent and a poor solvent, wherein the good solvent is one of dichloromethane, trichloromethane, dichloroethane and chlorobutane, the poor solvent is one of petroleum ether, cyclohexane, n-hexane, n-pentane, isopentane and isooctane, and the volume ratio of the good solvent to the poor solvent is 1:8 to 12.

According to the scheme, the mother liquor obtained in the step 1) is obtained in the process of preparing CPA by dehydrochlorination of CPA chloride.

According to the scheme, acetic anhydride is used as a reaction raw material and p-toluenesulfonic acid is used as a catalyst in the esterification reaction in the step 2); the mass ratio of the acetic anhydride to the CPA oily mother liquor is 1-2: 1, the mass ratio of the p-toluenesulfonic acid to the CPA oily mother liquor is 0.02-0.04: 1, the esterification reaction temperature is 30-40 ℃.

The method for treating the cyproterone acetate mother liquor specifically comprises the following steps:

1) Providing oily mother liquor generated in the CPA industrial production concentrated dry solvent in the CPA synthesis process, adding a mixed solvent, stirring and dissolving, and then filtering by using a normal-pressure chromatographic column, wherein an upper-section filter medium in the chromatographic column is diatomite, a lower-section filter medium in the chromatographic column is silica gel, the diatomite and the silica gel are separated by using filter cloth, after the filtration is finished, washing the chromatographic column by using the mixed solvent, combining a washing solution and a filtrate, and respectively collecting a combined solution and a silica gel layer;

2) Soaking and washing the silica gel layer with methanol, mixing the washed methanol solutions, evaporating to dryness, adding acetic anhydride and p-toluenesulfonic acid, controlling the temperature to react, adding trichloromethane and water after the reaction is completed, extracting, and washing the trichloromethane layer with water;

3) Concentrating the combined solution obtained in the step 1) to be dry to obtain a combined solution concentrate, adding the chloroform layer washed by water in the step 2) into the combined solution concentrate, stirring to obtain a mixture, then adding alkaline aluminum oxide and calcium hydroxide, and heating to react to prepare CPA.

According to the scheme, the mass of the mixed solvent in the step 1) is 1-2 times of that of the oily mother liquor in the process of adding the mixed solvent, stirring and dissolving.

According to the scheme, the filling height of the diatomite in the chromatographic column in the step 1) is 0.1-0.3 m, and the filling height of the silica gel is 0.5-1 m.

According to the scheme, in the step 1), the mixed solvent is used for washing the chromatographic column, and the mass of the mixed solvent is 3-6 times of that of the oily mother liquor.

According to the scheme, the silica gel layer in the step 2) is soaked and washed by methanol, and the amount of the methanol is preferably that the silica gel is completely immersed.

According to the scheme, the chloroform and water are added in the step 2) for extraction, and the mass ratio of the total amount of the chloroform used for extraction to the CPA oily mother liquor is 10-15: 1.

according to the scheme, the mass ratio of the alkaline alumina in the step 3) to the mixture is 0.8-1.5: 1, the mass ratio of the calcium hydroxide to the mixture is 0.1-0.2: 1, the reaction temperature is 40-60 ℃.

According to the scheme, the step 3) further comprises the steps of filtering after TLC detection reaction is completed, washing a filter cake with trichloromethane, combining filtrate washing liquor, evaporating to dryness, and recrystallizing to obtain a CPA pure product.

The method firstly utilizes the polarity difference between two impurities of CPA hydrolysis impurity and CPA chloride hydrolysis impurity and CPA chloride, and uses a mixed solvent with low polarity to elute the CPA and CPA chloride with low polarity along with the solvent in the step 1), while the CPA hydrolysis impurity and CPA chloride hydrolysis impurity with high polarity are adsorbed on a silica gel layer, and simultaneously the colloid is removed by filtration. In addition, the mother liquor has complex components and multiple components, and the mixed solvent greatly increases the solubility of each substance which is difficult to dissolve in the low-polarity mixed solvent, so that the substances can be dissolved in the low-polarity mixed solvent and then eluted.

And then carrying out 17-position re-esterification on the CPA hydrolysis impurity and CPA chloride hydrolysis impurity mixture in the silica gel layer to correspondingly obtain CPA and CPA chloride, and finally carrying out dehydrochlorination cyclization on the CPA chloride in the mixture under an alkaline condition, thereby skillfully realizing the efficient utilization of the cyproterone acetate mother liquor. In addition, CPA chloride in the mixture of the final dehydrochlorination cyclization only accounts for part, the alkali consumption is low, only 10-20% of the normal reaction is needed, the alkalinity of the system is greatly reduced, 17-bit hydrolysis impurities generated by the reaction are fewer compared with the normal dehydrochlorination cyclization reaction, and the recovery efficiency is improved.

The invention has the beneficial effects that:

the treatment method can convert impurities in the mother liquor into CPA, effectively separate and purify the CPA, ensure that the recovery rate of the CPA in the mother liquor is up to 70 percent, and the purity of the CPA obtained by separation is more than or equal to 99.5 percent, obtain good economic benefit on one hand, and reduce the pollution of hormone wastes to the environment on the other hand;

the operation is simple and convenient.

Drawings

FIG. 1 is a flow chart of the treatment of cyproterone acetate mother liquor in example 1 of the present invention.

Detailed Description

In order to make the technical solutions of the present invention better understood by those skilled in the art, the present invention is further described in detail with reference to the following examples.

Example 1

The process of treating cyproterone acetate mother liquor with the flow chart as shown in figure 1 includes the following steps:

sequentially filling diatomite and silica gel into a filter cylinder with a proper caliber, firstly filling the silica gel with a height of about 0.8m, adding filter cloth, separating, and then filling the diatomite with a height of about 0.2 m; taking 10kg of oily mother liquor after CPA industrial production concentrated dry solvent, adding 15kg of mixed solvent (dichloromethane: petroleum ether =1, volume ratio), stirring and dissolving, then filtering under normal pressure, adding 40kg of the same mixed solvent after filtering is finished, washing, merging washing liquid and filtrate, and respectively collecting merged liquid and a silica gel layer;

concentrating the combined solution to dryness to obtain combined solution concentrate, and storing for later use. Soaking and washing the silica gel layer with an appropriate amount of methanol for 3 times, combining methanol solutions, evaporating to dryness, adding 10kg of acetic anhydride, reacting 0.3kg of toluenesulfonic acid at the temperature of 35 ℃, monitoring by a TLC (thin layer chromatography) spot plate until the reaction is complete, adding 120kg of trichloromethane and water for extraction, and washing the trichloromethane layer with water for 3 times;

adding a trichloromethane layer into the combined liquid concentrate obtained in the previous step, stirring for dissolving, adding 8kg of alkaline alumina and 1kg of calcium hydroxide, heating to 50 ℃ for reacting for a certain time, performing TLC (detection by TLC) to detect that the reaction is complete, filtering (detection by reaction liquid: hydrolysis impurity is reduced to 0.19% from about 2% of normal production HPLC content), washing the filter cake with trichloromethane for 2 times, combining filtrate washing liquids, evaporating to dryness, recrystallizing with 95% ethanol to obtain 7.02kg of CPA, wherein the yield is 70.2%, and the purity is 99.6%.

Example 2

The method for treating the cyproterone acetate mother liquor comprises the following specific steps:

sequentially filling diatomite and silica gel into a filter cylinder with a proper caliber, firstly filling the silica gel with a height of about 0.7m, adding filter cloth for isolation, and then filling the diatomite with a height of about 0.2 m; taking 10kg of oily mother liquor after CPA industrial production concentrated dry solvent, adding 18kg of mixed solvent (trichloromethane: cyclohexane =1 10), stirring and dissolving, then filtering under normal pressure, adding 50kg of mixed solvent in the same proportion after filtering is finished, washing, combining washing liquid and filtrate, and respectively collecting combined liquid and a silica gel layer;

and concentrating the combined solution to dryness to obtain a combined solution concentrate, and storing for later use. Soaking and washing the silica gel layer with an appropriate amount of methanol for 3 times, combining methanol solutions, evaporating to dryness, adding 12kg of acetic anhydride, reacting 0.35kg of toluenesulfonic acid at the temperature of 30 ℃, monitoring by a TLC (thin layer chromatography) spot plate until the reaction is complete, adding 130kg of trichloromethane and water for extraction, and washing the trichloromethane layer with water for 3 times.

Adding a trichloromethane layer into the combined solution concentrate, stirring for dissolving, adding 10kg of alkaline alumina and 1.2kg of calcium hydroxide, heating to 55 ℃ for reacting for a certain time, performing TLC (detection of reaction solution: hydrolysis impurity is reduced to 0.22% from about 2% of normal production HPLC content) detection reaction, washing a filter cake for 2 times by using trichloromethane, combining filtrate washing solutions, evaporating to dryness, and recrystallizing by using 95% ethanol to obtain 6.93kg of CPA with the yield of 69.3% and the purity of 99.7%.

Example 3

sequentially filling diatomite and silica gel into a filter cylinder with a proper caliber, filling the silica gel with a height of about 0.5m, adding filter cloth for isolation, and then filling the diatomite with a height of about 0.3 m; taking 10kg of oily mother liquor after CPA industrial production concentrated dry solvent, adding 20kg of mixed solvent (dichloromethane: normal hexane =1: 10), stirring and dissolving, then filtering at normal pressure, adding 60kg of mixed solvent in the same proportion after filtering is finished, washing, combining washing liquid and filtrate, and respectively collecting combined liquid and a silica gel layer;

concentrating the combined solution to dryness to obtain combined solution concentrate, and storing for later use. Soaking and washing the silica gel layer with an appropriate amount of methanol for 3 times, combining methanol solutions, evaporating to dryness, adding 16kg of acetic anhydride, reacting 0.4kg of toluenesulfonic acid at the temperature of 30 ℃, monitoring by a TLC (thin layer chromatography) spot plate until the reaction is complete, adding 150kg of trichloromethane and water for extraction, and washing the trichloromethane layer with water for 3 times.

Adding a trichloromethane layer into the combined solution concentrate obtained in the previous step, stirring for dissolving, adding 14kg of alkaline alumina and 0.8kg of calcium hydroxide, heating to 45 ℃ for reaction for a certain time, detecting by TLC (detection of reaction solution: hydrolysis impurities are reduced to 0.17% from the content of normal production HPLC) after the reaction is completed, washing a filter cake for 2 times by using trichloromethane, drying the combined filtrate washing liquor by distillation, and recrystallizing by using 95% ethanol to obtain 7.08kg of CPA, wherein the yield is 70.8% and the purity is 99.7%.

Claims

1. The method for treating the cyproterone acetate mother liquor is characterized by comprising the following steps of:

1) Providing oily mother liquor generated in the CPA industrial production concentrated dry solvent in the CPA synthesis process, wherein the mother liquor contains CPA, CPA hydrolysis impurities, CPA chloride hydrolysis impurities and CPA chlorides, adding a mixed solvent into the mother liquor, and filtering by an atmospheric chromatographic column to remove a jelly, wherein an upper-stage filter medium in the chromatographic column is diatomite, a lower-stage filter medium in the chromatographic column is silica gel, the diatomite and the silica gel are separated by a filter cloth, after the filtration is finished, performing column chromatography elution by using the mixed solvent, and eluting the CPA and CPA chlorides with small polarity based on the polarity of the CPA and CPA chlorides and the polarity difference of the CPA hydrolysis impurities and CPA chloride hydrolysis impurities to obtain a washing liquid containing the CPA and CPA chlorides with small polarity for standby, wherein the mixed solvent is a mixture of a good solvent and a poor solvent, the good solvent is one or more than one of dichloromethane, trichloromethane, dichloroethane and chlorobutane, the poor solvent is one or more than one of petroleum ether, cyclohexane, n-hexane, n-pentane, isopentane and isooctane, the good solvent and the poor solvent are mixed in a volume ratio of 1:8 to 12;

2) Soaking and washing the silica gel layer with methanol, combining the washed methanol solutions, evaporating to dryness, collecting CPA hydrolyzed impurities and CPA chloride hydrolyzed impurities in a chromatographic column, and performing 17-position esterification reaction to correspondingly convert the CPA hydrolyzed impurities and the CPA chloride;

3) Mixing the washing solution of CPA and CPA chloride obtained in the step 1) with the CPA and CPA chloride obtained by conversion in the step 2), adding alkaline aluminum oxide and calcium hydroxide, dehydrochlorinating under alkaline conditions to carry out cyclization to prepare CPA,

。

2. the processing method according to claim 1, characterized in that: and step 1), adding a mixed solvent, and stirring to dissolve, wherein the mass of the mixed solvent is 1 to 2 times of that of the oily mother liquor.

3. The processing method according to claim 1, characterized in that: the filling height of the diatomite in the chromatographic column in the step 1) is 0.1-0.3m, and the filling height of the silica gel is 0.5-1m.

4. The processing method according to claim 1, characterized in that: and step 1) washing the chromatographic column by using the mixed solvent, wherein the mass of the mixed solvent is 3 to 6 times of that of the oily mother liquor.

5. The processing method according to claim 1, characterized in that: in the esterification reaction of the step 2), acetic anhydride is used as a reaction raw material, and p-toluenesulfonic acid is used as a catalyst; the mass ratio of the acetic anhydride to the oily mother liquor is 1 to 2:1, the mass ratio of the p-toluenesulfonic acid to the oily mother liquor is 0.02 to 0.04:1, the esterification reaction temperature is 30 to 40 ℃.

6. The processing method according to claim 1, characterized in that: and 2) soaking and washing the silica gel layer by using methanol, wherein the amount of the methanol is preferably that the silica gel is completely immersed.

7. The processing method according to claim 1, characterized in that: in step 1): after the filtration is finished, collecting filtrate filtered by the normal pressure chromatographic column, and combining the filtrate with washing liquid containing CPA and CPA chlorides with small polarity to obtain combined liquid;

the 17-bit esterification reaction in the step 2) is to add acetic anhydride and p-toluenesulfonic acid, control the temperature to react, add trichloromethane and water to extract after the reaction is complete, and wash a trichloromethane layer with water;

the step 3) is as follows: concentrating the combined solution obtained in the step 1) to be dry to obtain a combined solution concentrate, adding the chloroform layer washed in the step 2) into the combined solution concentrate, stirring to obtain a mixture, then adding alkaline alumina and calcium hydroxide, and heating to react to prepare CPA.

8. The processing method according to claim 7, characterized in that: and step 2), adding trichloromethane and water for extraction, wherein the mass ratio of the total amount of the trichloromethane used for extraction to the oily mother liquor is 10 to 15:1;

and 3) filtering after TLC detection reaction is completed, washing a filter cake by using trichloromethane, combining filtrate washing liquor, evaporating to dryness, and recrystallizing to obtain a CPA pure product.

9. The processing method according to claim 7, characterized in that: the mass ratio of the alkaline alumina to the mixture in the step 3) is 0.8 to 1.5:1, the mass ratio of the calcium hydroxide to the mixture is 0.1 to 0.2:1, the reaction temperature is 40 to 60 ℃.